Antihyperlipidemic compositions

ABSTRACT

The invention concerns cyclic imides, diones, reduced diones and analogs thereof which are useful as antihyperlipidemic agents to reduce serum cholesterol and trigylcerides.

BACKGROUND OF THE INVENTION

This invention relates to antihyperlipidemic or hypolipidemic agentswhich are useful in the control of mammalian diseases associated withincreased serum cholesterol or triglycerides.

SUMMARY OF THE INVENTION

It has been discovered that certain cyclic imides, diones and partiallyreduced diones are useful as antihyperlipidemic agents. These compoundsare represented by the formulas: ##STR1## .Iadd.orN-phthalimido-o-acetophenone .Iaddend.wherein X is aryl, cycloalkyl, orcycloalkylene containing up to ten carbon atoms; Y is CH or N; Z isalkyl containing up to 5 carbon atoms, carboxyl, carboalkoxyl whereinthe alkyl group contains up to 4 carbon atoms, acyl containing up to 4carbon atoms, alkylene, aryl, aralkyl or aralkylene; and n is 1 to 10.The invention includes further compounds wherein the group representedby X is replaced with at least one hydrogen on each of the carbon atomsadjacent the oxygen bearing functional groups. It includes, also,pharmaceutically acceptable acid addition salts of the compounds.Certain of the hydrogens, particularly those on aryl or cycloaliphaticrings may be substituted, for example, with a halogen atom or an alkylgroup containing up to 5 carbon atoms.

Many of the compounds within the scope of this invention are known,others are novel. None have previously been utilized or suggested ashypolipidemic agents. They have been found to significantly decreaseserum cholesterol, serum triglycerides and also to inhibit liver acetylcoenzyme A synthetase and carboxylase activity. Generally speaking, thebest activity is found with compounds in which the value of n is from 2to 4.

For hypolipidemic activity, the compounds were tested at 20 mg/kg/dayadministered I.P. to male CF₁ mice (˜30 g). On days 9 and 16 blood wascollected by tail-vein bleeding. Serum cholesterol was determined by theLiebermann-Burchard reaction. Serum triglyceride levels were determinedusing the Hycel commercial kits on a separate group of mice, which werebled on day 14.

Acetyl coenzyme A sythetase activity was determined by the method ofGoodridge, J.Biol. Chem 248,4318. Acetyl coenzyme A carboxylase activitywas determined by the method of Greenspan and Lowenstein, J.Biol. Chem.243,6273. The ability to lower serum cholesterol with the firstmentioned compound correlated with the ability to lower serumcholesterol. The ability to supress acetyl-CoA carboxylase activitypositively correlated with the lowering of serum triglycerides.

The results with some representative compounds of the invention areshown in Table 1. Table 2 shows the results of the enzyme studies withthe compounds of Table 1. Table 3 shows the results of similar studieswith still another group of compounds.

                                      TABLE 1                                     __________________________________________________________________________    The Effects of Imide Analogs on Serum Cholesterol and                         Triglyceride Levels of Male Mice                                                                   % Control                                                                                Serum                                                              Serum Cholesterol                                                                        Triglyceride                                  Compounds (N.sup.a = 6)                                                                            9th day                                                                            16th day                                                                            14th day                                      __________________________________________________________________________      Phthalimide        63 ± 13.sup.e                                                                   57 ± 7.sup.e                                                                     44 ± 8.sup.e                                 1-N--Phthalimidobutan-3-one                                                                      67 ± 11.sup.e                                                                   63 ± 7.sup.e                                                                     58 ± 7.sup.e                                 Succinimide        78 ± 9.sup.e                                                                    73 ± 12.sup.e                                                                    68 ± 7.sup.e                                 1-N--Succinimidobutan-3-one                                                                      90 ± 9                                                                          88 ± 7                                                                           79 ± 15                                      1,8-Naphthalimide  81 ± 6.sup.e                                                                    61 ± 7.sup.e                                                                     87 ± 12                                      1-N--(1,8-Naphthalimido)butan-3-one                                                              94 ± 12                                                                         86 ± 9                                                                           54 ± 15.sup.e                                Saccharin          68 ± 11.sup.e                                                                   67 ± 10.sup.e                                                                    51 ± 16.sup.e                                1-N--(o-Benzosulfimido)butan-3-one                                                               60 ± 8.sup.e                                                                    62 ± 6.sup.e                                                                     51 ± 7.sup.e                                 3-N--Phthalimidopropionic Acid                                                                   74 ± 10.sup.e                                                                   55 ±  12.sup.e                                                                   58 ± 9.sup.e                               10.                                                                             1-N--Phthalimidopropan-2-one                                                                     80 ± 16                                                                         67 ± 12.sup.e                                                                    48 ± 10.sup.e                                N--n-Butylphthalimide                                                                            72 ± 11.sup.e                                                                   54 ± 6.sup.e                                                                     82 ± 10                                      1% carboxymethylcellulose (control)                                                              100 ± 5.sup.b                                                                   100 ± 6.sup.c                                                                    100 ± 6.sup.d                              __________________________________________________________________________     .sup.a N = number of animals/group                                            .sup.b 118 mg % control value                                                 .sup.c 122 mg % control value                                                 .sup.d 137 mg % control value                                                 .sup.e p 0.001                                                           

                  TABLE 2                                                         ______________________________________                                        The In Vitro Effects of Imide Analogs on Enzymes of the                       Cholesterol and Triglyceride Synthetic Pathways                               % Control                                                                             Acetyl-CoA Citrate  Acetyl-CoA                                                                             Fatty Acid                               Compounds                                                                             Synthetase Lyase    Carboxylase                                                                            Synthetase                               (N.sup.a = 6.sup.d)                                                                   x ± S.D.                                                                              x ± S.D.                                                                            x ± S.D.                                                                            x ± S.D.                              ______________________________________                                         1      70 ± 8.sup.f                                                                          42 ± 6.sup.f                                                                        8 ± 4.sup.f                                                                         105 ± 8                                2      53 ± 12.sup.f                                                                         34 ± 4.sup.f                                                                        17 ± 3.sup.f                                                                        109 ± 7                                3      74 ± 6.sup.f                                                                          38 ± 3.sup.f                                                                        87 ± 7                                                                              98 ± 9                                 4      58 ± 6.sup.f                                                                          38 ± 7.sup.f                                                                        100 ± 5                                                                             81 ± 7.sup.g                           5      63 ± 9.sup.f                                                                          66 ± 6.sup.f                                                                        106 ± 6                                                                             86 ± 8                                 6      88 ± 5.sup.f                                                                          60 ± 5.sup.f                                                                        59 ± 8.sup.f                                                                        103 ± 4                                7      61 ± 7.sup.f                                                                          65 ±  6.sup.f                                                                       9 ± 2.sup.f                                                                         93 ± 5                                 8      74 ± 9.sup.f                                                                          47 ± 8.sup.f                                                                        12 ± 3.sup.f                                                                        104 ± 7                                9      57 ± 10.sup.f                                                                         87 ± 6.sup.g                                                                        18 ± 4.sup.f                                                                        107 ± 7                               10      58 ± 7.sup.f                                                                          76 ± 4.sup.f                                                                        24 ± 4.sup.f                                                                        91 ± 9                                11      44 ± 11.sup.f                                                                         72 ± 9.sup.f                                                                        76 ± 3.sup.f                                                                        75 ± 10.sup.g                         1% carbox-                                                                            100 ± 5.sup.b                                                                         100 ± 4.sup.c                                                                       100 ± 7.sup.d                                                                       100 ± 7.sup.e                         ymethyl-                                                                      cellulose                                                                     ______________________________________                                         .sup.a N = number of animals per group                                        .sup.b 28.5 mg acetyl CoA formed/gm wet tissue/30 min                         .sup.c 30.5 mg of citrate hydrolyzed/gm wet tissue/30 min                     .sup.d 32.010 dpm/gm wet tissue/30 min                                   

                                      TABLE 3                                     __________________________________________________________________________    Effects of Phthalimide Analogs on Serum Lipids in Mice.sup.a (N = 6)                             % Control        in vitro                                                     serum cholesterol                                                                        serum tri-                                                                          AcCoA lit.                                No.                                                                              Compound        9th day                                                                            16th day                                                                            glycerides                                                                          synthetase                                                                          ref.                                __________________________________________________________________________    1  potassium phthalimide                                                                         63 ± 6.sup.e                                                                    78 ± 3.sup.d                                                                     88 ± 4.sup.d                                                                     78 ± 6.sup.e                           2  N--methylphthalimide                                                                          74 ± 4.sup.e                                                                    74 ± 8.sup.d                                                                     68 ± 8.sup.c                                                                     66 ± 12.sup.e                                                                    1                                   3  N--ethylphthalimide                                                                           83 ± 4.sup.e                                                                    76 ± 2.sup.e                                                                     87 ± 5.sup.d                                                                     82 ± 5.sup.c                                                                     1                                   4  N--n-propylphthalimide                                                                        96 ± 4                                                                          74 ± 5                                                                           81 ± 9.sup.d                                                                     67 ± 3.sup.e                                                                     2                                   5  N--n-butylphthalimide                                                                         72 ± 10.sup.e                                                                   54 ± 6.sup.e                                                                     82 ± 16                                                                          82 ± 7.sup.d                                                                     3                                   6  N--n-pentylphthalimide                                                                        76 ± 5.sup.e                                                                    58 ± 3.sup.e                                                                     75 ± 16.sup.c                                                                    68 ±  6.sup.e                                                                    4                                   7  N--n-hexylphthalimide                                                                         96 ± 5                                                                          66 ± 4.sup.e                                                                     84 ± 8.sup.d                                                                     71 ± 12                                                                          3                                   8  N--n-heptylphthalimide                                                                        99 ± 7                                                                          72 ± 4.sup.e                                                                     84 ± 6.sup.d                                                                     71 ± 5.sup.e                                                                     5                                   9  N--n-octylphthalimide                                                                         101 ± 7                                                                         82 ± 3.sup.d                                                                     77 ± 4.sup.c                                                                     76 ± 7.sup.e                                                                     6                                   10 1-N--phthalimidopropan-2-one                                                                  80 ± 16.sup.b                                                                   67 ± 12.sup.e                                                                    48 ± 10.sup.e                                                                    58 ± 7.sup.e                                                                     7                                   11 1-N--phthalimidobutan-3-one                                                                   67 ± 11.sup.e                                                                   63 ± 7.sup.e                                                                     58 ± 7.sup.e                                                                     53 ± 12.sup.e                                                                    8                                   12 1-N--phthalimidopentan-4-one                                                                  71 ± 6.sup.e                                                                    63 ± 5.sup.e                                                                     59 ± 13.sup.e                                                                    62 ± 3.sup.e                                                                     9                                   13 1-N--phthalimidohexan-5-one                                                                   65 ± 9.sup.e                                                                    65 ± 7.sup.e                                                                     77 ± 5.sup.e                                                                     68 ± 6.sup.e                                                                     10                                  14 1-N--phthalimidoheptan-6-one                                                                  71 ± 6.sup.e                                                                    75 ± 12.sup.c                                                                    88 ± 5.sup.d                                                                     85 ± 3.sup.e                                                                     11                                  15 2-N--phthalimidoacetic acid                                                                   76 ±  7.sup.e                                                                   68 ± 7.sup.e                                                                     72 ± 9                                                                           72 ± 12.sup.e                                                                    12                                  16 3-N--phthalimidopropionic acid                                                                74 ± 7.sup.e                                                                    55 ± 11.sup.e                                                                    58 ± 10.sup.e                                                                    57 ± 7.sup.e                                                                     13                                  17 4-N--phthalimidobutyric acid                                                                  80 ± 7.sup.e                                                                    68 ± 6.sup.e                                                                     59 ± 14.sup.e                                                                    64 ± 12.sup.e                                                                    14                                  18 5-N--phthalimidovaleric                                                                       83 ± 9.sup.d                                                                    77 ± 4.sup.d                                                                     54 ± 5.sup.e                                                                     76 ± 8.sup.e                                                                     15                                  19 6-N--phthalimidocaproic acid                                                                  81 ± 6.sup.e                                                                    67 ± 3.sup.c                                                                     51 ± 12.sup.e                                                                    59 ± 9.sup.e                                                                     16                                  20 N--phthalimidomethyl acetate                                                                  61 ± 9.sup.e                                                                    62 ± 4.sup.e                                                                     57 ± 25.sup.e                                                                    62 ± 10.sup.e                                                                    17                                  21 N--phthalimidoethyl acetate                                                                   93 ± 13                                                                         95 ± 1.sup.e                                                                     82 ± 7.sup.d                                                                     81 ± 6.sup.e                                                                     18                                  22 N--phthalimidopropan-1-ol                                                                     102 ± 4                                                                         66 ± 2.sup.e                                                                     89 ± 9                                                                           84 ± 2.sup.h                              acetate                                                                    23 N--phthalimidobutan-1-ol                                                                      93 ±  9                                                                         66 ± 5.sup.e                                                                     88 ± 7.sup.b                                                                     83 ± 2.sup.e                                                                     19                                     acetate                                                                    24 1% carboxymethylcellulose.sup.j                                                               100 ± 2.sup.f                                                                   100 ± 11.sup.g                                                                   100 ± 6.sup.h                                                                    100 ± 6.sup.i                          __________________________________________________________________________     .sup.a N = number of mice per test group = 6                                  .sup.b p = 0.25.                                                              .sup.c p = 0.10.                                                              .sup.d p = 0.005.                                                             .sup.e p = 0.001.                                                             .sup.f 115 mg %.                                                              .sup.g 118 mg %.                                                              .sup.h 138 mg %.                                                              .sup.i 10.8 mg/g wet tissue.                                                  .sup.j Control.                                                          

In Table 3 literature references are given as illustrative of thegeneral procedures by which compounds of the invention are prepared. Thereferences are as follows:

1. Sakellarios, Helv. Chim. Acta 29, 1675 (1946)

2. Shoslakovskii et al, Bull Acad. Sci. USSR, Div. Chem. Sci., 455(1954)

3. Sterk et al, Arzneim-Forsch., 18, 798 (1968)

4. Meisenheimer et al, Justus Liebigs, Ann. Chem., 479,211(1930)

5. Vanags, Acta Univ. Latv., Kim, Fak. Serv., 4(8), 405(1939)

6. Salzberg, U.S. Pat. No. 2,101,323

7. Lanchaster et al, J. Org. Chem., 23, 1208(1958)

8. Abdel-Monen et al, J. Med. Chem., 17, 447(1974)

9. Baker et al, U.S. Pat. No. 2,625,549

10. Gabriel, Chem. Ber., 42, 1249(1909)

11. Billman et al, J. Am. Chem. Soc., 70, 1473(1948)

12. Chodroff et al, J. Am. Chem. Soc., 69, 256(1947)

13. Balenovic et al, J. Org. Chem. 19, 1591(1954)

14. Fujii et al, J. Med. Chem., 14, 354(1971)

15. Taub, U.S. Pat. No. 3,210,313

16. Nefhens et al, Recl. Trav. Chim. Pays-Bas, 82, 941(1963)

17. Rowland, U.S. Pat. No. 2,547,542

The disclosure of all of these publications are incorporated herein byreference.

The compounds used in the invention are not only highly active. Theyalso are non-toxic. The LD₅₀ of 1-N-phthalamidopropan-2-one, forexample, is higher than 2 g/kg in mice since no deaths were observed atthis concentration. Moreover, there is no evidence that the weight ofany of the major organs is altered as a result of treatment withcompounds used in the invention.

Unlike many hypolipidemic agents, the compounds used in the invention donot manifest estrogenic activities. For example, with1-N-phthalamidopropan-2-one, there was, in mice, no decrease in the sizeof the vas deferens, vesicular or testes after a 16 day treatment at 10(mg/kg)/day, nor did the drug demonstrate uterotropic effects inovariectomized immature females at 20 mg/kg. The compound caused nohypertophy of the adrenal, a characteristic of many previously knownhypercholesteremic agents.

When the compounds used in this invention are employed as hypolipidemicagents, they may be administered to warm-blooded mammals, e.g. mice,rats, rabbits, dogs, cats, monkeys, etc. alone or in combination withpharmacologically acceptable carriers, the proportion of which isdetermined by the solubility and chemical nature of the compounds,chosen route of administration and standard biological practice. Forexample, they may be administered orally in the form of tablets,capsules, lozenges, and the like containing such excipients as starch,milk sugar, and so forth. They may also be administered orally in theform of solutions or they may be injected parenterally. For parenteraladministration they may be used in the form of sterile solutioncontaining other solutes, for example, enough saline or glucose to makethe solution isotonic.

The dosage of the agents will vary with the form of administration andthe particular compound chosen. Furthermore, it will vary with theparticular subject under treatment. Generally, treatment is initiatedwith small dosages substantially less than the optimum dose of thecompound. Thereafter, the dosage is increased by small increments untilthe optimum effect under the circumstances is reached. In general, thecompounds of this invention are most desirably administered at aconcentration level that will generally afford effective results withoutcausing any harmful or deleterious side effects and preferably at alevel that is in the range of from about 10 mg to about 250 mg per kiloper day, although as mentioned above, variations will occur.

Typical compounds within the scope of this invention include:phthalimide; N-butylphthalimide; 1-N-phthalimidobutan-3-one;3-N-phthalimidopropionic acid; N-phthalimidomethyl acetate;1,8-naphthalimide;N-butyl-1-8-naphthalimide;1-N-(1',8'-naphthalimido)butan-3-one;3-N-(1',8'-naphthalimido)propionicacid;N-1,8-naphthalimidomethylacetate;indan-1,3-dione;2-butylindan-1,3-dione;1-(1',3'-diketo-2'-indanyl)butan-3-one;3-(1',3'-diketo-2'-indanyl)propionicacid;1,3-diketo-2-indanylmethyl acatate;saccharin; (o-benzosulfinimide);N-butylsaccharin;(N-butyl-o-benzosulfinimide);1-N-o-benzosulfinimidobutan-3-one;3 N-o-benzosulfinimidopropionic acid;N-o-benzosulfinimidomethyl acetate;hydroxyphthalamidine;N-butylhydroxyphthalamidine;1-N-hydroxyphthalamidinebutan-3-one; 3-N-hydroxyphthalamidinopropionicacid;N-hydroxyphthalamidinomethyl acetate; phthalamidine;N-butylphthalamidine;1-N-phthalamidinobutan-3-one;3-N-phthalamidinopropionicacid;N-phthalamidinomethylacetate;1-oxohydrindine;2-butyl-1-oxohydrindine;1-(1'oxo-2'-hydrindinyl)butan-3-one;3-(1'oxo-2'-hydrindinyl)propionicacid;1-oxo-2-hydrindinylmethyl acetate;succinimide;N-butylsuccinimide;1-N-succinimidobutan-3-one;3-N-succinimidopropionicacid;N-succinimidomethyl acetate;1,2-naphthalimide;N-hexyl-1,2-naphthalimide;1-N-(1',2'-naphthalamido)heptanoic acid;N-1',2'-naphthalamidomethylacetate;2,3-naphthalimide;N-hexyl-2,3-naphthalimide;1-N-(2',3'-naphthalamido)pentane-3-one;3-N-(2',3'-naphthalamido)hepanoicacid; N-2',3'-naphthalamidomethyl acetate;2-3-naphthosulfinimide;N-nonyl-2,3-naphthosulfinimide;1-N-(2',3'-naphthosulfinimido)hexane-2-one;4-N-(2',3'-naphthosulfinimido)butanoicacid;N-2',3'-naphthosulfinimidohexylbutyrate;1,8-naphthosulfinimide;N-nonyl-1,8-naphthosulfinimide;1-N-(1'8'-naphthosulfinimido)hexane-2-one;4-N-(1',8'-naphthosulfinimido)butanoicacid; N-1',8'-naphthosulfinimidohexyl butyrate.

As indicated above, compounds of the classes illustrated by the generalformulas are known, although not known for the valuable pharmacalogicalactivity disclosed herein. Accordingly general procedures for theirpreparation are known. Literature references to some of the proceduresare identified above. It may be helpful however for a betterunderstanding of the invention to briefly review some of the syntheticmethods.

One procedure which is generally applicable, once the closed ring systemhas been synthesized, is the Gabriel reaction in which an alkali metalsalt of the heterocyclic compound is reacted with an appropriate alkylhalide. This reaction is generally applicable because a hydrogenattached to a nitrogen or carbon adjacent a carbonyl group is acidic andeasily replaced by an alkali metal such as sadium or potassium. Thisinitial replacement normally takes place in alcoholic solution orsuspension by reaction of the basic compound with a sodium or potassiumalkoxide. The salt may be isolated, but it is not necessary to do so.

The salt is reacted in a reaction inert organic solvent with at least anequimolar quantity of the selected halide. Typically, the reaction takesplace at a temperature of from 70° C. to 150° C. during a period of from3 to 10 hours.

The product may be isolated by any convenient procedure. It may beisolated for example, by evaporation of the solvent and under vacuum,extraction of the residue with ahalogenated hydrocarbon or othervolatile solvent which is then suitably washed with aqueous alkali andwater, dried and evaporated to provide the desired product.

Alkyl halides, haloketones, haloesters, haloacids and haloalcohols whichcan be employed in the synthesis are available commercially or can bysynthesized by procedures well known in the art. For the production ofacids, it is preferred to carry out the original reaction with ahalocarbalkoxy ester and then form the acid by hydrolytic removal of thealkoxy group by treatment with aqueous acid or alkali.

N-carboxylic acid substituted compounds can also be prepared by reactionof the appropriate amino acid with an anhydride followed by ring closureby dehydration.

Y-substituted 3-butanones can be prepared by reaction of the appropriatesubstrate with methyl vinyl ketone in an alkaline media under theso-called Michael conditions.

Several additional synthetic procedures for placing the Y-substituentsare illustrated in the examples.

Compounds with one or two keto groups, for example,hydroxyphthalamidine, pthalamidine, 1-oxyhydrimidine and the like can bemade by known series of reactions.

Anthranilic acid, for example, can be converted to a 1-substitutedcompound of the invention by the following series of reactions:

1: Form o-cyanobenzoic acid by diazotization in the presence ofpotassium cyanide and a cuprous salt.

2: Form the corresponding aminomethylene compound by reduction withhydrogen under acidic conditions in the presence of a noble metalcatalyst such as palladium on carbon.

3: React resulting compound with an RX compound where X is halogen and Ris the Y-substituent.

4: Ring close in the presence of acid to produce a Y-substituted1-oxyhydrimidine.

An alternative procedure utilizes benzyl malonic ester, for example thediethyl ester as a starting compound followed by:

1: Replacement of the alpha hydrogen by reaction with an RX compoundwhere X is halogen and R is the Y-substituent.

2: Simultaneous hydrolysis and decarboxylation to produce an alpha orbeta phenylpropionic acid.

3: Convert to the acid chloride.

4: Ring closure under Friedel-Crafts conditions.

Y-substituted hydroxyphthalamidines and the analogous carbon compoundscan be produced by selective reduction of the corresponding diketcompounds, for example with potassium borohydride.

The acids and bases which can be used to prepare the pharmacologicallyacceptable acid addition and basic salts of this invention are thosecontaining non-toxic anions and cations. They include, for example,sodium, potassium and ammonium hydroxide, carbonate, bicarbonate andacetates; as well as hydrochloric, sulfuric, phosphoric, acetic, lactic,citric, tartaric, oxalic, succinic, maleic, gluconic, saccharic and likeacids. The salts are prepared by known procedures.

The following examples are given by way of illustration only and are notto be considered limitations of this invention many apparent variationsof which can be made without departing from its spirit or scope.

EXAMPLE 1 SYNTHESIS OF Y-ALKYL SUBSTITUTED COMPOUNDS

The synthesis of N-ethylphthalimide and n-amylphthalimide isillustrative of the general procedure by which N-alkyl and C-alkylcompounds within the scope of this invention can be prepred. Since thehydrogen to be replaced with an alkyl group is acidic it can be replacedwith an alkali metal by reaction with an alkoxide such as sodium orpotassium ethoxide. Those skilled in the art will recovnize theconditions of the ractions as the general conditions of the Gabrielsynthesis.

Method A

To 18.5 g (0.10 mol) of potassium phthalimide suspended in 100 ml of dryDMF, was added 0.11 mol of methyl-p-toluenesulfonate, ethyl iodide, or1-bromopentane. The reaction mixture was heated to 90°-100° C. for afive to eight hour period. The volatile material was removed underreduced pressure, 150 ml of CHCl₃ added to the residue, and the mixturewashed with 100 ml of 1 N aqueous NaOH and two 100 ml portions of H₂ O.The CHCl₃ layer was dried over Na₂ SO₄, evaporated, and the N-alkylphthalimide purified by recrystallization or distilled in vacuo.

EXAMPLE 2 SYNTHESIS OF Y-KETONE SUBSTITUTED COMPOUNDS

The synthesis of 1-N-phthalimidobutan-3-one and1-N-phthalimidohexan-5-one or 1-N-phthalimidoheptane-6-one under Michaelconditions or through an acetoacetic ester synthesis is illustrative ofgeneral procedures for the preparation of N-alkyl alkyl hetones withinthe scope of the invention.

1-N-Phthalimidobutan-3-one

A solution of 44.1 g (0.30) phthalimide in 200 ml of ethyl acetate,containing a catalytic amount of sodium ethoxide, was maintained at70°-78° C., whereupon 21.7 g (0.31 mol) of methyl vinyl ketone was addedover a 15 minute period. The resulting reaction mixture was refluxed anadditional 1.25 hr, then allowed to cool, and neutralized with aceticacid. Removal of the ethyl acetate under reduced pressure afforded 53 g(82%) 1-N-phthalimidobutan-3-one which melted at 114°-116° C. whenrecrystallized from 2-propanol.

1-N-Phthalimidohexan-5-one

Ethyl acetoacetate (8.67 g, 0.067 mol) in 132 ml ethanol was allowed toreact with 1.05 g (0.046 mol) of sodium. When the reaction was complete,9.52 g (0.032 mol) of 3-bromopropylphthalimide was added and theresulting solution refluxed 23 hrs. To the resulting yellow solution wasadded 113 ml of 4 NHCl and the product refluxed for four additionalhours then allowed to cool. The volatile material was removed underreduced pressure, 60 ml of H₂ O added to the residue and the resultingmixture extracted with four 140 ml portions of ethyl acetate. The ethylacetate solution was reduced to 100 ml, dried over MgSO₄, and distilledin vacuo to yield 3.5 g (45% 1-N-phthalimidohexan-5-one (bp 176°-186°C., 0.05 mmHg). m.p. 65°-67° C. (ether).

1-N-phthalimidoheptan-6-one

Ethyl acetoacetate, 3.41 g (0.026 mol) in 48 ml ethanol was reacted with0.40 g (0.01 mol) of sodium). When the reaction was complete, 4.0 g(9.914 mol) of 4-bromobutylphthalimide was added and the resultingsolution refluxed 22 hrs. To the resulting yellow solution was added 40ml of 4 N HCl and refluxing continued for 5 hrs. Upon cooling, thevolatile material was removed under reduced pressure 50 ml of H₂ O wasadded to the residue, and the resulting mixture extracted with four 150ml portions of ethyl acetate. The ethyl acetate solution was reduced to100 ml, dried over MgSO₄, and distilled under high vacuum to yield 1.75g (48%) 1-N-phthalimidoheptan-6-one (bp 166°-176° C., 0.25 mmHg). m.p.71.5°-74° C. (ether).

EXAMPLE 3 SYNTHESIS OF CARBOXYLIC ACID SUBSTITUTED COMPOUNDS

The synthesis of 3-N-phthalimide propionic, butyric, valeric and caproicacids by reaction of the corresponding anhydride with an aminosubstituted carboxylic acid followed by vinyl closure illustrates onegeneral method for preparing the carboxylic acid substituted componds ofthis invention.

To 7.41 g (0.50 mol) of phthalic anhydride dissolved in 50 ml ofacetone, was slowly added 0.05 mol of the appropriate amino acid, e.g.3-aminopropionic, 4-aminobutyric, 5-aminovaleric, or 6-aminocaproicacids, in 50 ml of acetone. After the addition was complete the acetonewas removed under reduced pressure to yield a white solid. The solid wassuspended in 100 ml toluene and the mixture refluxed. The water formedin the reaction was collected by azeotropic distillation in a Dean Starktrap. After 0.9 ml of water had been collected, the reaction mixture wasallowed to cool overnight to precipitate the phthalimido-N-alkanoicacid.

EXAMPLE 4 SYNTHESIS OF Y-CARBOALKOXY SUBSTITUTED COMPOUNDS

The synthesis of N-phthalimidopropan-1-ol acetate is illustrative of onegeneral procedure for preparing carbalkoxy substituted compounds withinthe scope of the invention by first forming an alcohol following thegeneral procedure of Example 3 followed by esterification.

3-N-Phthalimido-1-propanol was obtained by slowly adding 18.8 g (0.25mol) of 3-amino-1-propanol to 37 g (0.25 mol) of phthalic anhydride in200 ml of toluene. After the addition was complete, the reaction mixturewas refluxed until the theoretical amount of water had been collected ina Dean Stark trap. The reaction mixture was allowed to cool, and theproduct precipitated (46 g, 90%).

Acetate esters of the above alcohols and N-hydroxyethyl phthalimide wereobtained by acetylation with acetic anhydride and pyridine.N-Phthalimidopropan-1-ol acetate was obtained in 64% yield (m.p. 63°-65°C., MeOH). Anal. (C₁₃ H₁₃ NO₄)C,H.

EXAMPLE 5 SYNTHESIS OF Y-CARBOALKOXY SUBSTITUTED COMPOUNDS anothergeneral method of preparing esters within the scope of this inventionusing Gabriel conditions as further generally illustrated and describedin Example 1.

A mixture of 2.54 g (0.013 mol) 4-bromobutyl acetate, and 4.8 g (0.026mol) of potassium phthalimide was heated at 190°-200° C. for ten hours.Upon cooling, 50 ml of water was added, and the resulting mixtureextracted with three 150 ml portions of ethyl acetate. The volume of theethyl acetate layer was reduced to 100 ml, and this layer successivelywashed with 50 ml of 10% NaOH and 50 ml of H₂ O. The ethyl acetate wasseparated and evaporated to a light yellow oil which solidified uponaddition of ethanol and ice (1.5 g, 44%). m.p. 58.5°-60.5+ C. (EtOH-H₂O).

EXAMPLE 6 INJECTABLE COMPOSITION

A sufficient amount of 3-N-(1,8-naphthalamide)propionic acid to providea concentration of 10 mg/cc was formed into a micronized powder andsuspended in a 1% carboxymethyl cellulose mixture in sterile distilledwater.

EXAMPLE 7 ORAL SUSPENSION

A sufficient amount of 3-N-succinimide propionic acid was mixed with a10% suspension of tragacanth in sterile distilled water to provide asuspension containing 5 mg/cc of active agent. The composition was mixedin a colloid mill.

EXAMPLE 8 TABLETS

A mixture containing one part N-phthalimide O-acetophenone, 4 partslactose and 0.1 part starch was formed into a slug by compression. Theslug was processed through an oscillating granulator, 0.002 parts ofcalcium stearate added, and the mixture formed into tablets, each tabletcontaining 25 mg hypolipidemic agent, 100 mg lactose, 2.5 mg starch and0.5 mg calcium stearate.

What is claimed is:
 1. Antihyperlipidemic compositions comprising apharmaceutically acceptable carrier and, as the principal activeingredient, .Iadd.N-phthalimido-o-acetophenone or .Iaddend.a compound ofthe group represented by the .[.formulas.]. .Iadd.formulae.Iaddend.:##STR2## wherein X is aryl, cycloalkyl, or cycloalkylene containing upto ten carbon atoms; Y is CH or N; Z is alkyl containing up to fivecarbon atoms, carboxyl, carboalkoxyl wherein the alkyl group contains upto four carbon atoms, acyl containing up to four carbon atoms, alkylene,aryl, aralkyl or .[.aralhylene.]. .Iadd.aralkylene.Iaddend.; n is 1 to10; and further compounds wherein the group represented by X is replacedwith at least one hydrogen on each of the carbon atoms adjacent theoxygen bearing functional groups and .Iadd.wherein X is unsubstituted ormono-substituted with halogen or alkyl group containing up to 5 carbonatoms and .Iaddend.pharmaceutically acceptable acid.[.;.]. and alkalimetal addition salts thereof.
 2. A composition as in claim 1 wherein thecompound is 3-N-(1,8-naphthalamido)propionic acid.
 3. A composition asin claim 1 wherein the compound is 3-N-succinimido propionic acid.
 4. Acomposition as in claim 1 wherein the compound is 3-N-saccharinpropionic acid.
 5. A composition as in claim 1 wherein the compound isN-phthalimido o-acetophenone.
 6. A composition of claim 1 wherein thecompound is 3-N-phthalimidopropionic acid.
 7. A compound as in claim 1wherein n is 2 to
 4. 8. A method of controlling hyperlipidemia inmammals which comprises administering to said mammal an effective amountfor controlling hyperlipidemia of .Iadd.N-phthalimido-o-acetophenone or.Iaddend.a compound of the formula: ##STR3## wherein X is aryl,cycloalkyl, or cycloalkylene containing up to ten carbon atoms; Y is CHor N; Z is alkyl containing up to five carbon atoms, carboxyl,carboalkoxy wherein the alkyl group contains up to four carbon atoms,acyl containing up to four carbon atoms, alkylene, aryl, aralkyl oraralkylene; n is 1 to 10; and further compounds wherein the grouprepresented by X is replaced with at least one hydrogen on each of thecarbon atoms adjacent the oxygen bearing functional groups andpharmaceutically acceptable acid; and alkali metal addition saltsthereof.
 9. A method as in claim 8 wherein the compound is3-N-(1,8-naphthalamido)propionic acid.
 10. A method as in claim 8wherein the compound is 3-N-succinimido propionic acid.
 11. A method asin claim 8 wherein the compound is 3-N-saccharin propionic acid.
 12. Amethod as in claim 8 wherein the compound is N-phthalimidoo-acetophenone.
 13. A method as in claim 8 wherein the compound is3-N-phthalimidopropionic acid.
 14. A method as in claim 8 wherein thecompound is one in which n is 2 to 4.